AIDS in humans and macaques and fatal diseases characterized by long incubation and a progressive clinical course that stems from dysregulation of cells in the immune system and inflammatory/degenerative lesions in the nervous system. The pathogenesis of the syndrome is poorly understood but is known to be caused by lentiviruses, a type of retrovirus long recognized as the cause of chronic neurological diseases such as visna in sheep. We have been studying the molecular and immunopathogenesis of visna for several years and have identified many common biological properties between the human and ovine pathogens. Capitalizing on this experience, we have developed a broad strategy to probe the pathogenesis of experimental infection in macaques with the simian lentivirus (simian immunodeficiency virus) as a model for AIDS in humans. We will identify the types of cells infected with the virus, the stage of the virus life cycle in cells and the responses of cells to infection. Virus mutation with reference to development of antigenic variants and neurovirulent mutants will be assessed. The role of the macrophage as a host cell for virus replication and its function in antigen presentation will be examined in the medication of lesions. Antiviral antibodies will be examined functionally for forming complexes with virus that will be phagocytized by macrophages. Pathogenesis of the lesions will be examined from the hypothetical perspective of infection in local tissue macrophages, interaction of these cells with lymphocytes and resultant excess synthesis of cytokines such as the interferons, tumor necrosis factor, etc. which help to mediate the lesions. The mechanism of the neural lesion is hypothesized to originated with development of neurotropic variant viruses that are selected by the CNS in a manner similar to selection of antigenic variant viruses by neutralizing antibodies. The molecular basis of such variants will be examined. Interaction of virus with precursor cells in the bone marrow may prevent differentiation of specific cell lineages and may prevent synthesis of tropic hormones that are essential for differentiation of other cell populations. Infected stem cells may be reservoirs of the virus and disseminate the agents when the cells leave the bone marrow as monocytes and migrate to specific body sites such as the brain. The animal experiments outlined will be of a pilot nature, using small numbers of monkeys. More definitive experiments, using larger numbers of macaques will be planned when concepts in pathogenesis become more concrete.